Cyclosporine A nephrotoxicity: role of thromboxane and reactive oxygen species.
The main adverse effect of cyclosporine A (CyA) is nephrotoxicity. CyA increases urinary concentrations of thromboxane A2 (TXA2), a potent vasoconstrictor that can be involved in kidney failure induced by CyA. Furthermore, it has been postulated that a relationship exists between oxygen free radicals and the synthesis of arachidonate metabolites in experimental models of CyA nephrotoxicity. We studied the effect of vitamin E (VitE), an oxygen free radical scavenger, on renal function, on glomerular synthesis of thromboxane B2 (TXB2), and on free radicals in rats treated with CyA. Four groups of male Wistar rats were studied: (1) a control group; (2) a group given VitE at 0.05 mg/dl in drinking water for 25 days; (3) a group given CyA at 50 mg/kg body weight/day orally for 10 days; and (3) a group given Vit E + CyA, in which rats were provided with drinking water containing VitE for 15 days and afterwards were treated with VitE and CyA for 10 days. Renal function parameters and glomerular synthesis of TXB2, superoxide anion (02.-), malondialdehyde (MDA), and hydrogen peroxide (H202) were evaluated. CyA decreased body weight, caused deterioration of kidney function and increased glomerular synthesis of TXB2, O2.-, MDA, and H202. Pretreatment with VitE prevented the effects of CyA on kidney function and decreased glomerular synthesis of these mediators. In conclusion, CyA induced glomerular synthesis of reactive oxygen species (ROS) and TxB2. Pretreatment with VitE inhibited acute renal failure induced by CyA, probably by scavenging free radicals and by inhibiting the synthesis of TXB2.
Parra
T
T
Research Unit and Nephrology Section, Hospital General Universitario de Guadalajara, Madrid, Spain.
de Arriba
G
G
Arribas
I
I
Perez de Lema
G
G
Rodriguez-Puyol
D
D
Rodriguez-Puyol
M
M
D000818:Animals; D001835:Body Weight; D016572:Cyclosporine / Q000633:toxicity*; D016166:Free Radical Scavengers / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced*; D007678:Kidney Glomerulus / Q000378:metabolism; D008054:Lipid Peroxides / Q000378:metabolism; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000502:physiology*; D013481:Superoxides / Q000378:metabolism; D013928:Thromboxane A2 / Q000378:metabolism*; D013929:Thromboxane B2 / Q000652:urine; D014810:Vitamin E / Q000494:pharmacology
D016166:Free Radical Scavengers; D008054:Lipid Peroxides; D017382:Reactive Oxygen Species; D013481:Superoxides; D014810:Vitamin E; D013929:Thromboxane B2; D013928:Thromboxane A2; D016572:Cyclosporine; D006861:Hydrogen Peroxide